Is BTN3A2 p.Val116Ile (c.346G>A) pathogenic?

BTN3A2 p.Val116Ile (c.346G>A) is classified Uncertain significance in BTN3A2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-26). AlphaMissense: likely benign (0.0708); Very rare (popmax 0.00838%, amr).

How common is BTN3A2 p.Val116Ile (c.346G>A) in the general population?

BTN3A2 p.Val116Ile (c.346G>A) is very rare (popmax 0.00838%, amr) (gnomAD).

What do computational predictors say about BTN3A2 p.Val116Ile (c.346G>A)?

AlphaMissense predicts likely benign (score 0.0708) — an in-silico prediction, not a clinical call.

BTN3A2 p.Val116Ile

c.346G>A · VCV3993600

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0708 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00838%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0708	likely benign
REVEL	0.259	benign-leaning
SaProt	LLR -7.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.4	GERP -3.7
Regional constraint	o/e 0.15	constrained · MANE · 1,654 bp · p 1.1e-17 · regional, not allelic
Overall
CADD	18.48	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00838% Admixed American · 5/59,698 alleles

Filtering AF 0.00325% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00208%

Overall 0.00124% 20/1,607,322 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00838%	11,940
African / African-American	0.00403%	24,823
East Asian	0.00223%	44,808
Finnishnot grpmax-eligible	0.00157%	63,812
European (non-Finnish)	0.00085%	117,669

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BTN3A2
Protein: p.Val116Ile
Coding: c.346G>A
MANE Select: NM_007047
Type: single nucleotide variant
Location: chr6:26368825 (GRCh38)
Gene constraint: LOEUF 1.043 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 90.23 · 18 PDB
Residue 116: a disulfide bond; the ig-like v-type domain

Full BTN3A2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

BTN3A2 p.Ala110Thr Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala182Asp Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala192Val Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala233Gly Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala245Thr Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala264Thr Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala266Val Uncertain significance ★ ⚠ same type
BTN3A2 p.Ala48Thr Uncertain significance ★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/btn3a2-p-val116ile (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown